Chasing Novo and Lilly: The obesity drugs that could challenge Wegovy and Zepbound
8 min read
One study can start a pharmaceutical revolution.
Four years ago, a large clinical trial run by Novo Nordisk showed a drug called semaglutide helped people with obesity lose, on average, around 15% of their weight. The results far exceeded what prior studies of other treatments had suggested was possible pharmaceutically, sparking a rush to research that has quickly reshaped the obesity drug field.
Demand for semaglutide, now sold in nine countries by Novo as Wegovy, has surged to such heights the company can’t keep up. Physicians see Wegovy and other drugs like it as powerful treatments for obesity as well as its many related health consequences.
Analysts forecast annual sales of this new class of medicines to surpass $100 billion by early next decade. Drugmakers are investing billions of dollars in an attempt to get a piece of that market, as would-be competitors test new ways to regulate metabolism and spur weight loss.
Some 120 drugs are now in clinical development for obesity, according to a recent report from Iqvia, from Wegovy mimics to psilocybin and coated glucose beads. More than one-third work by stimulating gut hormones like GLP-1 — the target of Wegovy.
To succeed, they’ll likely have to at least match the double-digit weight loss numbers shown in testing for Wegovy and Zepbound, a rival drug from Eli Lilly approved in the U.S. last year. Here’s where the field stands:
How well do current drugs work?
Until the early 2010s, physicians had only a few drugs they could prescribe for obesity, one of which, phentermine, was first approved in 1959. A spurt of research in the early 2000s led to the 2012 and 2014 approvals of three more treatments: Qsymia, Belviq and Contrave.
While those drugs showed greater weight loss than placebo in testing, their effects were largely seen as unexceptional, resulting in limited uptake. Qsymia in particular was linked with safety issues, including the risk of fetal toxicity and heart problems. Belviq, meanwhile, was withdrawn in 2020 due to an association with higher rates of cancer.
Their launches came around the time the the first GLP-1 drugs arrived on the market for diabetes. Novo, after seeing the weight loss effects of its diabetes drug Victoza, developed a daily injectable version specifically for obesity. Dubbed Saxenda, it had only a modest impact on weight and never caught on widely, either.
Novo was quick to advance successor GLP-1s, however. While working on the weekly injection that became the diabetes drug Ozempic, Novo simultaneously studied a formulation for weight loss. Importantly, the company also committed to a longer-term plan designed to prove the expected weight loss benefit would help protect the heart.
Both bets paid off. Treatment with Wegovy, which contains the same active drug as Ozempic, reduced weight by an average of 10% to 16% across a range of studies — approaching levels typically achieved via bariatric surgery.
A large study, meanwhile, proved weight loss from Wegovy reduced the relative risk of heart attacks, strokes or cardiovascular death by 20%, compared to a placebo. U.S. approval for this use last year made Wegovy the only weight loss drug that can be marketed as having such benefits. The new label helped push Medicare, which is prohibited by law from reimbursing for obesity treatment, into covering Wegovy for some people.
Yet Lilly may ultimately have an upper hand with its rival drug Zepbound. On a surface-level comparison, Zepbound led to greater average weight loss in testing, showing reductions between 13% and 21%, depending on the study and dose. Additionally, a larger share of participants in Lilly’s studies experienced at least 10% weight loss than did participants in Novo’s testing of Wegovy.
The two medicines have never been compared head to head in a trial, however, so no definitive conclusion can be drawn about their relative weight loss benefits.
Lilly doesn’t have heart data to match Novo yet. A similarly large Zepbound trial, called SURPASS-CVOT, should produce data in 2025, potentially putting an expanded label for the drug two years behind Wegovy. Lilly is testing Zepbound against an active medicine, its older GLP-1 drug Trulicity, however, which could strengthen its case.
Zepbound is likely to show a similar heart benefit to Wegovy, according to Angela Fitch, president of the Obesity Medical Association and chief medical officer at the Massachusetts clinic Knownwell.
“There’s been a positive effect on cardiovascular health from the less potent GLP-1s,” she noted.
What could new drugs improve upon?
Novo and Lilly have set the bar high with Wegovy and Zepbound, so much so that some in the industry are describing those drugs’ benefits as “table stakes” for would-be rivals. Competitors will need to show an advantage in efficacy, safety or convenience.
Current GLP-1 drugs for weight loss are delivered via an under-the-skin injection. (Although Novo does sell an oral version of Wegovy for diabetes.) A pill with similar potency could be attractive to people who’d prefer to avoid needles. However, peptide-based drugs like GLP-1s are difficult to deliver through the digestive tract, where they are broken down by enzymes and absorbed only slowly due to their relatively large size.
Key GLP-1 and related drugs in development
| Company | Drug | Status | Type | Key dates |
|---|---|---|---|---|
| Eli Lilly | Zepbound | Marketed | GLP-1/GIP agonist | Late 2024 heart outcomes data readout |
| Eli Lilly | orforglipron | Phase 3 | Oral GLP-1 agonist | 2025 data readouts |
| Eli Lilly | retatrutide | Phase 3 | GLP-1/GIP/Glucagon agonist | 2026 data readouts |
| Novo Nordisk | Oral semaglutide | Phase 3 | GLP-1 agonist | 2024 FDA filing, adtl. data readouts |
| Novo Nordisk | cagrilintide/semaglutide | Phase 3 | GLP-1/amylin agonist | Late 2024/2025 data readout |
| Boehringer / Zealand | survodutide | Phase 3 | GLP-1/glucagon agonist | Late 2025 data readout |
| Pfizer | danuglipron | Phase 2 | Oral GLP-1 agonist | 2024 data on once-daily version |
| Amgen | maridebart cafraglutide | Phase 2 | GLP-1 agonist, GIP antagonist | Late 2024 data readout |
| Viking Therapeutics | VK2735 | Phase 1/2 | GLP-1 agonist | 2024 oral Phase 2 trial start |
| Roche | RG 6641 (CT-868) | Phase 2 | GLP-1/GIP agonist | 2024 data readout |
| Roche | RG 6640 (CT-388) | Phase 1 | GLP-1/GIP agonist | 2024 data readout |
| Roche | RG 6652 (CT-996) | Phase 1 | GLP-1 agonist | 2024 data readout |
SOURCE: Company disclosures
Another approach could target the drugs’ known side effects. GLP-1s are often associated with gastrointestinal problems such as nausea and vomiting. There are also concerns, based on an animal and biomarker data, of a possible link to certain types of cancer. This could make other proposed mechanisms for stimulating weight loss, such as blocking cannabinoid or opioid receptors, more attractive.
Companies hoping to make inroads on Wegovy and Zepbound might also try to improve on how readily existing GLP-1s are absorbed and used by the body. Both Novo and Lilly have had difficulty manufacturing enough of the drugs, and a formulation that’s more easily taken up by the body could allow for lower doses.
Drug developers are looking, too, at how to preserve lean mass, as the rapid weight loss from current GLP-1s also leads to unwanted reduction in muscle tissue. Patients taking Zepbound lost 11% of their muscle mass in a substudy of a major trial that led to its FDA approval, for example.
Shrinking muscle mass is particularly concerning for older people for whom less strength could increase frailty. And if people regain weight after significant losses, the subsequent gains tend to be disproportionately fat.
Lean mass also plays an important role in metabolism, as muscles burn more energy at rest than fatty tissue and secrete a hormone that spurs glucose uptake.
“We tend to think of a muscle as a motor — it moves things from one place to another,” said Peter Ackerman, vice president for clinical development at Biohaven, which is developing a muscle-building drug in both obesity and the rare disease spinal muscular atrophy. “I think it has many more important roles to play in our overall health.”
What’s next?
Lilly and Novo aim to maintain their current hold on the market. Both companies are testing several experimental drugs with the goal of launching oral versions or even more effective treatments than their current products.
Novo is already close to completing a Phase 3 trial program testing an oral form of Wegovy. It also has in late-stage development a combination of Wegovy with a compound called cagrilintide that acts on a gut hormone called amylin.
Lilly has two drugs in Phase 3: an oral GLP-1 dubbed orforglipron that is approaching key data readouts next year and an injectable treatment called retatrutide that stimulates GLP-1, GIP and a third hormone known as glucagon. Results in obesity are due in 2026.
Lilly has four experimental drugs in Phase 1 or 2, while Novo has five.
“[Lilly and Novo] cover all the bases,” said Clive Meanwell, CEO of Metsera, a newly launched startup that has two obesity drugs in clinical testing. “Our belief is it’s going to be a portfolio play, with mix and match, with different clinical circumstances and different markets.”
Select non-GLP1 drugs in clinical development
| Company | Drug(s) | Status | Type | Key dates |
|---|---|---|---|---|
| Eli Lilly | bimagrumab | Phase 2 | activin inhibitor | 2024 data readout |
| Novo Nordisk | INV-202 | Phase 2 | CB1 inhibitor | 2025 data readout |
| Shionogi | S-309309 | Phase 2 | MGAT2 inhibitor | 2024 data readout |
| Kallyope | K-757, K-833 | Phase 2 | Nutrient receptor agonist | 2024 data readout |
| Amgen | AMG 786 | Phase 1 | Unknown | Mid-2024 data readout |
| Regeneron | trevogrumab, garetosmab | Phase 1 | myostatin, activin A inhibitors | Mid-2024 Phase 2 trial start |
| Biohaven | taldefgrobep alfa | Phase 1 | myostatin inhibitor | 2024 Phase 2 trial start |
| Skye Bioscience | nimacimab | Phase 1 | CB1 inhibitor | Mid-2024 Phase 2 trial start |
SOURCE: Company disclosures
The rush by drugmakers large and small to test GLP-1 rivals means clinical trial data could soon prove which approaches work best.
Already, some companies have been forced to adjust. For example, Pfizer developed two non-peptide oral drugs targeting GLP-1, but both returned mixed results. One was scrapped because of safety concerns. The other remains in testing, but Pfizer is reworking its dosing because of a high rate of gastrointestinal side effects.
Viking Therapeutics has had better luck. The biotech reported encouraging early data for a GIP-GLP1 combination it’s developing as both a shot and a pill. The drug appears more tolerable than Wegovy or Zepound.
A Phase 2 trial of the pill is expected to begin later this year. In the meantime, Viking’s valuation has swelled to around $8 billion, suggesting investors see it as an acquisition target for larger drugmakers looking to build their pipeline.
Zealand Pharma and Boehringer Ingelheim, meanwhile, are partnered on a drug called survodutide that targets GLP-1 and glucagon and has also produced encouraging early results. Phase 3 study data could come late next year.
Investors are also watching closely two drugs from Amgen called AMG 133 and AMG 786. The first activates GLP-1, like Wegovy and Zepbound, but blocks another hormone called GIP — opposite of Zepbound’s mechanism.The big biotech hasn’t disclosed exactly how AMG 786 works.
Regeneron Pharmaceuticals, Biohaven and Lilly are exploring treatments designed to preserve lean mass, results from which could reveal how much this strategy might contribute.
Further afield are companies like Japan’s Shionogi and startups Kallyope and Skye Bioscience. The former drugmaker is working on an inhibitor of an enzyme involved in dietary fat absorption, while Kallyope’s drugs target gut proteins that themselves stimulate hormones like GLP-1. Skye is testing a drug designed to regulate appetite by blocking certain proteins in the nervous system.
